rs35077384

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001385875.1(ZFYVE27):c.572G>T(p.Gly191Val) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,614,016 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.025 ( 112 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 150 hom. )

Consequence

ZFYVE27
NM_001385875.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:7

Conservation

PhyloP100: 3.60

Variant links:

Genes affected

ZFYVE27 (HGNC:26559): (zinc finger FYVE-type containing 27) This gene encodes a protein with several transmembrane domains, a Rab11-binding domain and a lipid-binding FYVE finger domain. The encoded protein appears to promote neurite formation. A mutation in this gene has been reported to be associated with hereditary spastic paraplegia, however the pathogenicity of the mutation, which may simply represent a polymorphism, is unclear. [provided by RefSeq, Mar 2010]

ZFYVE27 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030166805).

BP6

Variant 10-97749494-G-T is Benign according to our data. Variant chr10-97749494-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1289.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=1}. Variant chr10-97749494-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE27	NM_001385875.1 linkuse as main transcript	c.572G>T	p.Gly191Val	missense_variant	6/13	ENST00000684270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE27	ENST00000684270.1 linkuse as main transcript	c.572G>T	p.Gly191Val	missense_variant	6/13		NM_001385875.1	A1	Q5T4F4-1

Frequencies

GnomAD3 genomes

AF:

0.0255

AC:

3877

AN:

152126

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0740

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00748

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.00987

AC:

2483

AN:

251480

Hom.:

AF XY:

0.00880

AC XY:

1196

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0792

Gnomad AMR exome

AF:

0.00572

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00174

Gnomad SAS exome

AF:

0.00464

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00638

Gnomad OTH exome

AF:

0.00993

GnomAD4 exome

AF:

0.00871

AC:

12733

AN:

1461772

Hom.:

150

Cov.:

AF XY:

0.00842

AC XY:

6122

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0786

Gnomad4 AMR exome

AF:

0.00642

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00705

Gnomad4 SAS exome

AF:

0.00485

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00745

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.0255

AC:

3880

AN:

152244

Hom.:

112

Cov.:

AF XY:

0.0238

AC XY:

1771

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0739

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00483

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00747

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.0286

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.0726

AC:

320

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.0109

AC:

1329

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00905

EpiControl

AF:

0.00812

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 33

Pathogenic:1Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Spastic tetraparesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 28, 2013

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2021

This variant is associated with the following publications: (PMID: 18606302, 20981092, 16826525, 27884173) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.016

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D

MetaRNN

Benign

0.0030

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

D;N;N;N;D;.;N

REVEL

Benign

0.17

Sift

Uncertain

0.0070

D;D;D;D;D;.;D

Sift4G

Benign

0.10

T;T;T;T;T;T;T

Polyphen

0.58, 0.19, 0.29, 0.26

.;.;.;P;B;B;B

Vest4

0.43

ClinPred

0.018

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over